The present invention relates to the area of platinum drugs. In particular, it relates to an improved process for preparing platinum complexes having the general formula (Ia) or (Ib): 
wherein:
L and Lxe2x80x2 may be the same or different, provided that Lxe2x80x2 may be NH3, but L may not be NH3; and
L and Lxe2x80x2 are each an amine or substituted amine that coordinates to the Pt atom through a nitrogen atom and is a heterocyclic amine or heteroaromatic amine or is represented by NRRxe2x80x2Rxe2x80x3, wherein R, Rxe2x80x2, or Rxe2x80x3 are independently selected from the group consisting of:
hydrogen, substituted or unsubstituted straight, branched or cyclic aliphatic, aryl, nonaromatic or aromatic heterocyclic groups; and
preferably L is a substituted amine wherein the substituent sterically hinders access of the Pt atom to a DNA strand of cell, preferably a tumor cell; and
A may be the same or different and is a halogen or a leaving group such as hydroxy, alkoxide, carboxylate and may be the same or different or form a bi-dentate carboxylate, phosphoncarboxylate, diphosphonate or sulfate; and
Y is a halogen, hydroxy, carboxylate, carbamate or carbonate ester.
U.S. Pat. No. 4,329,299 and 5,665,771 describe platinum compounds and their usefulness as antitumor drugs. These two patents disclose platinum compounds that encompass complexes of the formula cis-[PtA2(Lxe2x80x2)(L)] and c,t,c-[PtA2Y2(Lxe2x80x2)(L)], where A is a leaving group such as halogen, hydroxyl or carboxylate, L is an amine coordinated through the nitrogen atom and Lxe2x80x2 is an ammonium or substituted amine. The process for preparing these complexes disclosed in the patents are known in the art (Hydes, P. C. U.S. Pat. No. 4,329,299 (1982); Murrer, B. A. U.S. Pat. No. 5,665,771 (1997); Braddock, P. D.; Connors, T. A.; Jones, M.; Khokhar, A. R.; Melzack, D. H.; Tobe, M. L. Chem.-Biol. Interactions 1975, 11, 145-161; and Giandomenico, C. M.; Abrams, M. J.; Murrer, B. A.; Vollano, J. F.; Rheinheimer, M. I.; Wyer, S. B.; Bossard, G. E.; Higgins (III), J. D. Inorg. Chem. 1995, 34, 1015-1021). This process is illustrated in FIG. 1 with the synthesis of cis-[PtCl2(NH3)(L)] and c,t,c-[PtCl2(OH)2(NH3)(L)] as examples. From the readily available and commonly used K2[PtCl4] starting material, the synthesis of cis-[PtCl2(NH3)(L)] involves four steps and the synthesis of c,t,c-[PtCl2Y2(NH3)(L)] requires five steps. The synthesis of these complexes according to the process known in the art gives low overall yield. U.S. Pat. No. 4,329,299 discloses an overall yield from K2[PtCl4] of less than 8%, while overall yields of 20-30% have been reported in U.S. Pat. No. 5,665,771 and in the literature (Khokhar et al. and Giandomenico et al.). The low overall yield is due to the many stages involved in the process and to the difficult and low yielding conversion of [PtCl2(NH3)2] to [PtCl3(NH3)]xe2x88x92, which requires the use of expensive Pt catalyst. The synthesis of K[PtCl3(NH3)] from [PtCl2(NH3)2] is also not particularly robust and large scale synthesis producing K[PtCl3(NH3)] of consistent quality is difficult to achieve. The process described above further requires the use of silver and iodide ions, and generates silver and iodide contaminated waste products.
U.S. Pat. No. 4,533,502 and UK Patent GB 2137198A disclose a synthetic process to prepare [PtX2(L)(Lxe2x80x2)] where L and Lxe2x80x2 are ligands bonded through amine nitrogen and Lxe2x89xa0Lxe2x80x2 (Rochon, F. D.; Kong, P.-C. UK Patent GB2137198A (1984) and Rochon, F. D.; Kong, P.-C. U.S. Pat. No. 4,533,502 (1985)). The process is known in the art and the details of this synthetic process has been published (Courtot, P.; Rumin, R.; Peron, A.; Girault, J. P. J. Organometallic Chem. 1978, 145, 343-357 and Rochon, F. D.; Kong, P.-C. Can. J. Chem. 1986, 64, 1894-1896). FIG. 2 illustrates the process with [PtCl2(L)(Lxe2x80x2)] as an example. From K2[PtCl4], the process disclosed in U.S. Pat. No. 4,533,502 and UK Patent GB 2137198A involves 4 steps and the isolation of 3 intermediate products. The oligomer intermediate product is represented by [PtLI2]x where x=2 to 4; multiple oligomer species are possible. The overall yield from K2[PtCl4] was not disclosed in the patent. Silver and iodide ions are used in the process and corresponding silver and iodide contaminated wastes are generated.
[PtCl3L]xe2x88x92, where L is an amine other than NH3, represent an intermediate in the present invention. The preparation of [PtCl3L]xe2x88x92 from a dilute solution of K2[PtCl4] in dimethylformamide (DMF) where L are pyridine and pyridine derivatives has been reported (Rochon, F. D.; Kong, P.-C. Can. J. Chem. 1978, 56, 441-445 and Rochon, F. D.; Beauchamp, A. L.; Bensimon, C. Can. J. Chem. 1996, 74, 2121-2130). The preparation of [PtCl3L]xe2x88x92 in solvents other than DMF or H2O, or with amine other than pyridine and pyridine derivatives have not been reported. The synthesis of K[PtCl3L] in DMF as reported in the literature was performed at 65-80xc2x0 C. and the yields of the isolated product ranged from 40% to 90% depending on the pyridine derivative. Synthesis of [PtCl3L]xe2x88x92 in DMF can produce reactive or unstable Pt DMF complexes that could interfere with subsequent reactions or decompose to give insoluble black Pt impurities. For example in Can. J. Chem. 1978, 56, 441, Rochon et al reported the precipitation of insoluble black material when K[PtCl3(2,6-dimethylpyridine)] was dissolved in aqueous solution. It was also reported that an oily paste that contained [PtCl2(DMF)(pyridine derivative)] and other impurities was obtained during the isolation of K[PtCl3(4-methylpyridine)] and K[PtCl3(pyridine)]. Examples of [PtCl2(DMF)L] complexes have been reported (Kong, P.-C.; Rochon, F. D.; Can. J. Chem. 1979, 57, 682-684; Rochon, F. D.; Kong, P.-C.; Melanson, R. Can. J. Chem. 1980, 58, 97-101; and Rochon, F. D.; Melanson, R.; Doyon, M.; Butler, I. S. Inorg. Chem. 1994, 33, 4485-4493).
Citation of the above documents is not intended as an admission that any of the foregoing is pertinent prior art. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the correctness of the dates or contents of these documents. Further, all documents referred to throughout this application are incorporated in their entirety by reference herein. Specifically, the present application claims benefit of priority to U.S. provisional patent application serial No. 60/128,939, which was filed on Apr. 13, 1999 and which provisional patent application is incorporated in its entirety by reference herein.
The present invention describes a more efficient and economical process for preparing Pt complexes of the form cis-[PtA2(Lxe2x80x2)(L)] (formula Ia) and c,t,c-[PtA2Y2(Lxe2x80x2)(L)] (formula Ib) directly from inexpensive and readily available platinum starting material, preferably tetrahaloplatinite like [PtCl4]2xe2x88x92 or [PtBr4]2xe2x88x92.
wherein:
L and Lxe2x80x2 may be the same or different, provided that Lxe2x80x2 may be NH3, but L may not be NH3; and
L and Lxe2x80x2 are each an amine or substituted amine that coordinates to the Pt atom through a nitrogen atom and is a heterocyclic amine or heteroaromatic amine or is represented by NRRxe2x80x2Rxe2x80x3, wherein R, Rxe2x80x2, or Rxe2x80x3 are independently selected from the group consisting of:
hydrogen, substituted or unsubstituted straight, branched or cyclic aliphatic, aryl, nonaromatic or aromatic heterocyclic groups; and
preferably L is a substituted amine wherein the substituent sterically hinders access of the Pt atom to a DNA strand of cell, preferably a tumor cell; and
A may be the same or different and is a halogen or a leaving group such as hydroxy, alkoxide, carboxylatate and may be the same or different or form a bi-dentate carboxylate, phosphoncarboxylate, diphosphonate or sulfate; and
Y is a halogen, hydroxy, carboxylate, carbamate or carbonate ester.
In one embodiment, the process of the present invention is preferred for preparation of compound of formula Ia.
Terms as used herein are based upon their art recognised meaning and from the present disclosure should be clearly understood by the ordinary skilled artisan. For sake of clarity, terms may also have particular meaning as would be clear from their use in context. For example, a ligand is an ion or molecule bound to and considered bonded to a metal atom or ion. Mono-dentate means having one position through which covalent or coordinate bonds with the metal may be formed. Bi-dentate means having two positions through which covalent or coordinate bonds with the metal may be formed. The present invention preferably is a mono-dentate coordination of the L and Lxe2x80x2 amine through the nitrogen atom to Pt. Further, xe2x80x9csterically hinderedxe2x80x9d is used according to common usage in the art. xe2x80x9cSterically hindered aminexe2x80x9d therefore refers to an amine component that because of its size or bulk hinders or interferes with rotation or other function or property of any other component of the Pt complexes disclosed herein. The processes of the present invention are preferably used to prepare the compounds described in U.S. Pat. No. 5,665,771, (particularly the sterically hindered amines derived by formula Ia in ""771 patent) which is incorporated in its entirety herein and specifically the definitions of substitutent groups as disclosed therein are specifically incorporated by reference herein. By the term xe2x80x9csubstitutedxe2x80x9d what is meant herein, when in reference to both L and Lxe2x80x2 as a nitrogen-linked heterocyclic amine(s) or heteroaromatic amine(s), is that a substitute group is independently selected from the group consisting of: hydrogen, substituted or unsubstituted straight, branched or cyclic aliphatic, aryl, nonaromatic or aromatic heterocyclic groups; and preferably where L is a substituted amine, the substituent thereby sterically hinders access of the Pt atom to a DNA strand of cell, preferably a tumour cell. Examples of such substituted L or Lxe2x80x2, include, but are not limited to: alkyl amines which may include: methyl amine; dimethyl amine; tributyl amine; di-isopropyl amine; aryl amines which may include: aniline, toluidine, aminonaphthalene and aminoanthracene; heterocyclic amines which may include: piperidine, piperazine, and pyrrolidine; and heteroaromatic amines which may include: pyridine, pyrazoles, imidazoles, oxazoles, iso-oxazoles; pyrimidine, and pyrazine. Other substituents are available to the ordinary skilled artisan who would readily appreciate that such other substitutents may be employed in the present invention in a manner consistent with the present disclosure.
More specifically, for example, in the case of substituted cyclic amines, the substituent may be lower alkyl or alkoxy of 1 to 4 carbon atoms, (especially methyl or methoxy), halo, (especially chloro or bromo), or aryl, (especially benzyl). The substituent may itself be substituted by lower alkyl or halo. By the term xe2x80x9clower alkylxe2x80x9d is meant an alkyl group with from 1 to 6 carbon atoms. The cyclic amine may carry other substituents either adjacent to the coordinating nitrogen atom or elsewhere on the ring. Other substituents include electron-withdrawing or electron-donating substituents such as nitro and alkoxy eg methoxy. If the cyclic amine is a fused ring system where the fused ring is an aromatic ring in positions 2 and 3 of the cyclic amine, no other substituent is necessary, although a substituent may be present. It can also be envisioned that this invention may be used to make trans isomers. For the preferred embodiment, this invention is used to make the cis isomers.
To illustrate the invention, the synthesis of cis-[PtCl2(NH3)(L)] and c,t,c-[PtCl2(OH)2(NH3)(L)] from [PtCl4]2xe2x88x92 are used as examples. The congeners cis-[PtBr2(NH3)(L)] and c,t,c-[PtBr2(OH)2(NH3)(L)] can also be prepared in the same manner from [PtBr4]2xe2x88x92.
For the preparation of cis-[PtCl2(NH3)(L)], the improved process involves two steps with the first step being the conversion of a suspension or concentrated solution of [PtCl4]2xe2x88x92 to [PtCl3L]xe2x88x92 in aprotic solvents. The second step converts a suspension or concentrated solution of [PtCl3L]xe2x88x92 to cis-[PtCl2(NH3)(L)] in ammonium hydroxide solution. Compared to the synthetic processes currently used in the art, the improved process has fewer synthetic steps, fewer isolated products, requires smaller volumes of ecologically harmful solvents, generates less metal contaminated wastes and produces cis-[PtCl2(NH3)(L)] with higher overall yields. It also does not require the use of silver and iodide ions, and does not generate silver and iodide contaminated wastes. All steps in the process are robust, reproducible and consistently generate products of the same quality.
The first step of the improved process is the reaction of [PtCl4]2xe2x88x92 with the amine L under appropriate conditions in a first solvent to form [PtCl3L]xe2x88x92. The potassium salt of [PtCl4]2xe2x88x92, which is the most readily available, is commonly employed. However, other salts of [PtCl4]2xe2x88x92 could also be used. Appropriate conditions herein shall mean those reaction conditions that promote and facilitate the chemical reaction as disclosed and claimed. Specifically, the present invention provides that such appropriate conditions include, but are not limited to: temperature; pH; concentration of reactants; degree of agitation; mesh size of reactants; and other such conditions facilitating the disclosed chemical reactions. However, other appropriate conditions would be those familiar to the ordinary skilled artisan that result in the steps of the disclosed chemical reactions. To aid in the dissolution of K2[PtCl4], it is preferred to use finely ground K2[PtCl4] powder. It is preferred that K2[PtCl4] be less than or equal to about 240 xcexcM in size. It is more preferable to have K2[PtCl4] be less than or equal to about 100 xcexcM in size. In the reaction, 1 to 1.3 equivalents of the amine is reacted with 1 equivalent of K2[PtCl4]. More preferably, 1 to 1.2 equivalent of the amine is used. It is most preferred to have 1.05 to 1.15 equivalent of the amine react with 1 equivalent of K2[PtCl4]. Using high equivalents of the amine increase the rate of the reaction but could also increase the formation of side products and lower the yield of the reaction. Additionally, the amine, L, is added to the reaction mixture in small portions over a period of time. Preferably, the amine is added in two or more equal amounts or more preferably in 4 or more amounts.
The reaction can be performed at a temperature of about 30-100xc2x0 C. but it is more preferred to perform the reaction at about 40-70xc2x0 C. Most preferably, a temperature range of about 50-65xc2x0 C. is used. In general, the higher the reaction temperature the greater the rate of the reaction between [PtCl4]2xe2x88x92 and the amine. However a high reaction temperature could increase the formation of side products or allow the formation of reactive and unstable Pt impurities. In solvents that are capable of coordinating to metal atoms like DMF, reaction temperature greater than or equal to about 60xc2x0 C. may promote the formation of Pt solvent complexes, which would decompose or interfere with the next step of the process.
The reaction is performed in aprotic solvents. It is preferred that the solvent be anhydrous containing less than about 25% water but a water content of less than about 10% is preferred. Most preferably, a water content of less than about 3% is desired. The reaction can be performed in aprotic solvents such as acetone, chloroform, dichloromethane, dimethylacetamide, dimethylformamide and N-methylpyrrolidinone. N-methylpyrrolidinone is the most preferred solvent.
The first reaction step is performed at a ratio that is less than about (15 ml solvent)/(1 mmole platinum). A preferred embodiment of the present invention contemplates a ratio of solvent (ml) to Pt (mmol) that is about 3-6:1. However, in a more preferred embodiment of the present method, the first reaction step is performed at a solvent to Pt ratio of about 1-2:1.
The synthesis of [PtCl3L]xe2x88x92 in dimethylformamide (DMF), where L are pyridine or pyridine derivatives, are known in the literature (Rochon, F. D.; Kong, P.-C. Can. J. Chem. 1978, 56, 441-445; Rochon, F. D.; Beauchamp, A. L.; Bensimon, C. Can. J. Chem. 1996, 74, 2121-2130). For the synthesis of K[PtCl3(L)], K[PtCl3(2-picoline)] is used as an illustrative example to compare the published method with the method disclosed in this invention. In the published method, the isolation of K[PtCl3(2-picoline)] requires two separate steps during each of which solvents under reduced pressure are evaporated. In the evaporation of DMF under reduced pressure, heating at 40xc2x0 C. is required. In large-scale industrial synthesis, the evaporation of solvents under reduced pressure, particularly with heating is a costly and time consuming procedure. In our preferred procedure, the synthesis and isolation of K[PtCl3(2-picoline)] does not require the evaporation of solvents and does not require the transfer of the material from one solvent to another. The method disclosed in this invention is more efficient and is better suited for large-scale industrial production of the compound. The two methods produce K[PtCl3(2-picoline)] in comparable yields and quality. Infrared and NMR spectroscopic data of K[PtCl3(2-picoline)] produced using the method known in the art and with the method disclosed in this invention are shown on FIGS. 4 and 5. The synthesis of [PtCl3L]xe2x88x92 in other aprotic solvents such as acetone, chloroform, dichloromethane and N-methylpyrrolidinone was demonstrated in this invention.
The coordination of solvent molecules to Pt causing the formation of reactive or unstable Pt species poses a problem to the process described in this invention. In the published method (Rochon, F. D.; Kong, P.-C. Can. J. Chem. 1978, 56, 441-445), [PtCl2(DMF)(pyridine derivative)] and other impurities were reported in the synthesis of [PtCl3(pyridine derivative)]. In this invention, we disclose a temperature range in which the formation of undesired species such as [PtCl2(DMF)(pyridine derivative)] is minimized. The formation of black precipitate during the isolation of the product is indicative of the presence of reactive Pt impurities. Using the synthesis of K[PtCl3(2-picoline)] in dimethylformamide as an example, no insoluble black precipitates are observed when the synthesis is performed below about 60xc2x0 C. In our most preferred procedure, a reaction temperature of about 50-65xc2x0 C. is used in the first reaction step. However, any temperature at which the formation of undesired species or reaction product impurities such as [PtCl2(DMF)(pyridine derivative)] is minimized ( less than 10%) or eliminated is contemplated by the present method.
Conversion of [PtCl3L]xe2x88x92 to [PtCl2(NH3)L] in aqueous ammonia hydroxide is used to illustrate step 2 of the present invention. Step 2 is the reaction of a suspension or concentrated solution of [PtCl3L]xe2x88x92 with NH3 in a second solvent to produce [PtCl2(NH3)L]. The synthesis of [PtCl2(NH3)L] is performed at about 30-60xc2x0 C. in ammonium hydroxide solution. It is more preferred to perform the reaction at about 35-55xc2x0 C., while about 40-50xc2x0 C. is most preferred reaction temperature. In general, a higher reaction temperature shortens the reaction time but could also promote the formation of Pt multi ammine/amine side products. The greater formation of side products decreases the yield of the reaction.
The reaction is performed at about pH 7-14. A pH of about 7-12 is more preferred, while a pH of 8-10 is the most preferred. Performing the reaction at about pH greater than  to 10 can again result in lower yields due to the increased formation of Pt multi amine side products.
The reaction is performed at a concentration of 1 g of K[PtCl3L] per 3-10 mL of solvent. A concentration of 1 g of K[PtCl3L] per 4-8 mL of solvent is more preferable, while a concentration of 1 g of K[PtCl3L] per 5-7 mL of solvent is most preferred. It was unexpected that performing the reaction at a high concentration would efficiently generate the product at a high yield. The reaction can be performed at a much more dilute concentration but the yield of the reaction was low due to the formation of side products. Larger volumes of solvents and more dilute concentration also requires the disposal of larger volumes of ecologically harmful solvents and waste. It is preferred to perform this reaction in strictly aqueous solutions. However, combination of organic and aqueous solvents can also be used. Specifically, the present method provides that the second reacting step 1b) is performed at a solvent to platinum ratio of less than or equal to about 5:1 (ml solvent)/(mmole platinum.). The second step of the process is performed with a NH3/Pt ratio range of about 3 to 7. A NH3/Pt ratio or about 4 to 6 is preferred, while a NH3/Pt ratio of about 4.5 to 5.5 is most preferred. The present method provides that the second reacting step 1b) is performed at a molar ratio of free base form of Lxe2x80x2 to platinum between about 3:1 and 1:1. Large excess NH3 decreases the time of reaction but may also increase the formation of Pt multi ammine/amine side products.
From cis-[PtA2(NH3)(L)], c,t,c-[PtA2(OH)2(NH3)(L)] can be prepared by reacting a suspension of cis-[PtA2(NH3)(L)] with hydrogen peroxide. Other Pt(IV) complexes of the formula c,t,c-[PtA2Y2(NH3)(L)] using methods known in the art, where Y is a halogen, hydroxy, carboxylate, carbamate or carbonate ester, other than where both Y are hydroxide, can be prepared from c,t,c-[PtA2(OH)2(NH3)(L)].
The examples used to illustrate the preparation of cis-[PtCl2(NH3)(L)] and c,t,c-[PtCl2(OH)2(NH3)(L)] can also be used to prepare compounds of the general formula of cis-[PtA2(L)(Lxe2x80x2)] and c,t,c-[PtA2Y2(L)(Lxe2x80x2)], where L and Lxe2x80x2 may be the same or different, provided that Lxe2x80x2 may be NH3, but L may not be NH3; and L and Lxe2x80x2 are each an amine or substituted amine that coordinates to the Pt atom through a nitrogen atom and is a heterocyclic amine or heteroaromatic amine or is represented by NRRxe2x80x2Rxe2x80x3, wherein R, Rxe2x80x2, or Rxe2x80x3 are independently selected from the group consisting of: hydrogen, substituted or unsubstituted straight, branched or cyclic aliphatic, aryl, nonaromatic or aromatic heterocyclic groups and preferably L is a substituted amine wherein the substituent sterically hinders access of the Pt atom to a DNA strand of cell, preferably a tumor cell. A may be the same or different and may be a halogen or a leaving group such as hydroxy, alkoxide, carboxylate or form a bi-dentate carboxylate, phosphoncarboxylate, diphosphonate or sulfate; and Y is a halogen, hydroxy, carboxylate, carbamate or carbonate ester.
For complexes Ia or Ib, methods are known in the art for converting Ligand A to different leaving group(s) such as halide, hydroxy, alkoxide, or mono-dentate carboxylate, or bi-dentate carboxylate, or bi-dentate phosphonocarboxylate, or bi-dentate phosphonate, or bi-dentate sulphate. Examples of such transformations are depicted in Equation 1 and Equation 2. Many other permutations and combinations of the leaving group conversions can be conceived that would lead to useful complexes. The method of preparation of the disclosed intermediates would be useful for the preparation of all these compounds.
Equation 1. Method of Preparing a Complex of Formula Ia Where the two Leaving Groups A are Halides and are Different. 
Equation 2. Conversion of both ligands A (where A=halide to form a new compound where both A is the same and form a bi-dentate carboxylate. 
Having now generally described the invention, the same will be more readily understood through reference to the following examples which are provided by way of illustration, and are not intended to be limiting of the present invention, unless specified.